Mechanical strain is an important stimulus for maintaining bone mass, but the proximate molecular target responsible for mechanosensing is not known. The objective of this application is to test the novel hypothesis that the primary cilium-polycystin complex functions as a mechanosensor in osteoblasts and osteocytes in postnatal bone. We have discovered that polycystin 1 (PC1), a cell-surface transmembrane receptor encoded by PKD1, polycystin 2 (PC2), a calcium channel encoded by PKD2, and primary cilium, a single, non-motile, membrane-covered cell surface projection, are present and co-localize in osteoblasts/osteocytes. Based on the known ability of primary cilium, PC1 and PC2 to assemble into a mechanosensing complex and our preliminary studies showing that PC1 mutant mice have impaired bone and osteoblastic response to mechanical loading in vivo and in vitro and that the Osteocalcin-Cre mediated selective deletion of PKD1 from bone results in osteopenia in adult mice, we propose that the primary cilium/polycystin complex is a key mechanosensor in osteoblasts and osteocytes. To further establish the importance of primary cilium and the PC1/PC2 complex in the osteoblast lineage, we will use mouse genetic approaches to create animal models that selectively lack primary cilium and polycystins only in osteoblasts and osteocytes. Specifically, we will use the Cre-conditional (lox-P) system to achieve osteoblast/osteocyte-specific inactivation of PKD1 and primary cilium by crossing Osteocalcin and Dentin Matrix Protein 1 (DMP1) promoter driven Cre mice with floxed PKD1 and KIF3A mice. By examining the response of these animals to mechanical loading and unloading in vivo and the response of osteoblasts and osteocytes derived from these mice to mechanical strain in vitro, we will elucidate the mechanosensing role of primary cilium and PKD1 in bone and identify signaling pathways linking this mechanosensing complex to anabolic responses. These studies will define the function of primary cilium and polycystins in osteoblasts and osteocytes and will contribute to a better understanding of molecular mechanisms underlying mechanical load-induced bone formation. PUBLIC HEALTH RELEVANCE: The positive outcome of these investigations will herald a new area of investigation in bone biology research that will impact fundamentally on our understanding of how bone senses mechanical loading and will provide new insights into prevention of bone loss due to immobilization and microgravity. Development of pharmacological approaches to increased bone mass might be developed by targeting cilia/polycystins in bone, thereby offering the potential of new treatments for osteopenic disorders.